Comprehensive Splice Pattern Analysis for Previously Reported OCRL Splicing Variants and Their Phenotypic Contributions
Introduction: Two distinct phenotypes of Dent disease-2 and Lowe syndrome are caused by oculocerebrorenal syndrome of Lowe (OCRL) abnormality. Previous genetic studies demonstrated that truncating variants in exons 1 to 7 results in Dent disease-2 and in exons 8 to 24, result in Lowe syndrome. Recen...
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Elsevier
2025-05-01
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| Series: | Kidney International Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2468024925001135 |
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| author | Rini Rossanti Eri Okada Nana Sakakibara Ryota Suzuki Yuta Inoki Yuta Ichikawa Yu Tanaka Hideaki Kitakado Chika Ueda Atsushi Kondo Yuya Aoto China Nagano Tomoko Horinouchi Tomohiko Yamamura Shingo Ishimori Kandai Nozu |
| author_facet | Rini Rossanti Eri Okada Nana Sakakibara Ryota Suzuki Yuta Inoki Yuta Ichikawa Yu Tanaka Hideaki Kitakado Chika Ueda Atsushi Kondo Yuya Aoto China Nagano Tomoko Horinouchi Tomohiko Yamamura Shingo Ishimori Kandai Nozu |
| author_sort | Rini Rossanti |
| collection | DOAJ |
| description | Introduction: Two distinct phenotypes of Dent disease-2 and Lowe syndrome are caused by oculocerebrorenal syndrome of Lowe (OCRL) abnormality. Previous genetic studies demonstrated that truncating variants in exons 1 to 7 results in Dent disease-2 and in exons 8 to 24, result in Lowe syndrome. Recently, we successfully identified a functional OCRL isoform, whose altered initiation codons (Met187 and Met206) in exon 8 can affect the OCRL-truncating variant phenotypes. However, the association between OCRL splicing variants and phenotypes is poorly understood. Methods: We performed a detailed splicing pattern analysis of previously reported 28 OCRL splicing variants obtained from the Human Gene Mutation Database. We assessed the variant consequences at the mRNA level using an in vitro splicing assay with a minigene system, and examined their compatibility with in silico algorithms and correlation with disease phenotypes. Results: Aberrant splicing was confirmed in all 27 variants, except for 1, in which splicing could not be experimentally confirmed in the minigene system, and therefore could not be concluded with certainty. Splicing variants in OCRL exons 1 to 7 resulted in Dent disease-2, and in exons 9 to 24 resulted in Lowe syndrome. In 1 case, c.561-2 A > G in exon 8 demonstrated Dent disease-2. Conclusion: This study provides significant data on the pathogenicity of OCRL splicing variants and genotype-phenotype correlations. In c.561-2 A > G, the latter altered initiation codon of the OCRL isoform (Met206) was preserved, potentially indicating the Dent disease-2 phenotype. This result supports our recent finding regarding the altered initiation codons in exon 8 of the OCRL isoform. |
| format | Article |
| id | doaj-art-d7534bc074da4dd298aac637484ee5c3 |
| institution | Kabale University |
| issn | 2468-0249 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
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| series | Kidney International Reports |
| spelling | doaj-art-d7534bc074da4dd298aac637484ee5c32025-08-20T03:45:07ZengElsevierKidney International Reports2468-02492025-05-011051509151710.1016/j.ekir.2025.02.023Comprehensive Splice Pattern Analysis for Previously Reported OCRL Splicing Variants and Their Phenotypic ContributionsRini Rossanti0Eri Okada1Nana Sakakibara2Ryota Suzuki3Yuta Inoki4Yuta Ichikawa5Yu Tanaka6Hideaki Kitakado7Chika Ueda8Atsushi Kondo9Yuya Aoto10China Nagano11Tomoko Horinouchi12Tomohiko Yamamura13Shingo Ishimori14Kandai Nozu15Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan; Department of Child Health, Nephrology Division, Dr. Hasan Sadikin General Hospital/Faculty of Medicine, Universitas Padjadjaran, Bandung, IndonesiaDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan; Correspondence: Nana Sakakibara, Department of Pediatrics, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo, Kobe, Hyogo, Japan.Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan; Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanDepartment of Pediatrics, Kobe University Graduate School of Medicine, Kobe, JapanIntroduction: Two distinct phenotypes of Dent disease-2 and Lowe syndrome are caused by oculocerebrorenal syndrome of Lowe (OCRL) abnormality. Previous genetic studies demonstrated that truncating variants in exons 1 to 7 results in Dent disease-2 and in exons 8 to 24, result in Lowe syndrome. Recently, we successfully identified a functional OCRL isoform, whose altered initiation codons (Met187 and Met206) in exon 8 can affect the OCRL-truncating variant phenotypes. However, the association between OCRL splicing variants and phenotypes is poorly understood. Methods: We performed a detailed splicing pattern analysis of previously reported 28 OCRL splicing variants obtained from the Human Gene Mutation Database. We assessed the variant consequences at the mRNA level using an in vitro splicing assay with a minigene system, and examined their compatibility with in silico algorithms and correlation with disease phenotypes. Results: Aberrant splicing was confirmed in all 27 variants, except for 1, in which splicing could not be experimentally confirmed in the minigene system, and therefore could not be concluded with certainty. Splicing variants in OCRL exons 1 to 7 resulted in Dent disease-2, and in exons 9 to 24 resulted in Lowe syndrome. In 1 case, c.561-2 A > G in exon 8 demonstrated Dent disease-2. Conclusion: This study provides significant data on the pathogenicity of OCRL splicing variants and genotype-phenotype correlations. In c.561-2 A > G, the latter altered initiation codon of the OCRL isoform (Met206) was preserved, potentially indicating the Dent disease-2 phenotype. This result supports our recent finding regarding the altered initiation codons in exon 8 of the OCRL isoform.http://www.sciencedirect.com/science/article/pii/S2468024925001135Dent disease-2isoformLowe syndromeminigene systemOCRLSplicing |
| spellingShingle | Rini Rossanti Eri Okada Nana Sakakibara Ryota Suzuki Yuta Inoki Yuta Ichikawa Yu Tanaka Hideaki Kitakado Chika Ueda Atsushi Kondo Yuya Aoto China Nagano Tomoko Horinouchi Tomohiko Yamamura Shingo Ishimori Kandai Nozu Comprehensive Splice Pattern Analysis for Previously Reported OCRL Splicing Variants and Their Phenotypic Contributions Kidney International Reports Dent disease-2 isoform Lowe syndrome minigene system OCRL Splicing |
| title | Comprehensive Splice Pattern Analysis for Previously Reported OCRL Splicing Variants and Their Phenotypic Contributions |
| title_full | Comprehensive Splice Pattern Analysis for Previously Reported OCRL Splicing Variants and Their Phenotypic Contributions |
| title_fullStr | Comprehensive Splice Pattern Analysis for Previously Reported OCRL Splicing Variants and Their Phenotypic Contributions |
| title_full_unstemmed | Comprehensive Splice Pattern Analysis for Previously Reported OCRL Splicing Variants and Their Phenotypic Contributions |
| title_short | Comprehensive Splice Pattern Analysis for Previously Reported OCRL Splicing Variants and Their Phenotypic Contributions |
| title_sort | comprehensive splice pattern analysis for previously reported ocrl splicing variants and their phenotypic contributions |
| topic | Dent disease-2 isoform Lowe syndrome minigene system OCRL Splicing |
| url | http://www.sciencedirect.com/science/article/pii/S2468024925001135 |
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